Cognition is the most important determinant of functional ability and quality of life. Diminished cognitive capacity can cause significant psychological, social, and economic hardship and adversely impact a person's ability to benefit from treatment for other medical problems. The most rapidly rising threat to cognitive health in US adults is the clustering of obesity, hypertension, hyperglycemia and dyslipidemia in a single person, a condition known as metabolic syndrome (MetS). A staggering 34-45% of US adults currently fulfill criteria for MetS. While we have some information about each of the disrupted peripheral physiological mechanisms in turn, very little is known about the central mechanisms that connect the syndrome to brain health and cognition. The goal of the proposed work is to explore the underlying neural mechanisms of MetS-related brain vulnerability in midlife, before clinically significant and permanent cognitive dysfunction has developed. Understanding the pre-clinical stages of disease has the enormous advantage of presenting opportunities for early intervention, a task with much higher prospect of success than striving to restore lost function later in life. The specific aims of this project will be accomplished by examining behavioral performance, cerebral metabolism, and brain response to a cognitive challenge in cognitively intact middle-aged adults with and without MetS in a cross sectional between groups design. We propose to first define the unique patterns of cerebrovascular response to cognition associated with MetS using functional magnetic resonance imaging (fMRI);then, to characterize the changes in neuronal viability associated with midlife MetS using neurospectroscopy (1H MRS);and finally, to test if neurochemical alterations mediate the observed alterations in functional brain activation in response to a cognitive challenge using path analysis. PUBLIC HEALTH RELEVANCE: Cognition is the most important determinant of functional ability and quality of life. The most rapidly rising threat to cognitive health in US adults is the clustering of obesity, hypertension, hyperglycemia and dyslipidemia in a single person, a condition known as metabolic syndrome (MetS), yet little is known about the mechanisms that connect the syndrome to brain health. The goal of the proposed work is to explore the underlying neural mechanisms of MetS-related brain vulnerability in midlife, in order to guide efforts to prevent and treat late-life cognitive impairment, and ensure successful aging for our growing population of elderly.